Plaster containing fentanyl

ABSTRACT

The invention relates to a transdermal, therapeutic system comprising a coating layer and an adhesive matrix having a fentanyl content.

The invention concerns a transdermal therapeutic system with a coverlayer, an adhesive matrix that contains fentanyl as the activeingredient, and a removable protective layer.

Fentanyl (fentanylum, fentanil) was already patented in 1984 for use ina transdermal patch (U.S. Pat. No. 4,588,580). In the interim it hasproven extremely effective in the treatment of severe and/or chronicpain states, especially in the treatment of postoperative pain and painassociated with cancer. Side effects of fentanyl are the typical sideeffects observed with this class of substances, the opioids, namely,nausea, circulatory problems, constipation or pruritus, andlife-threatening respiratory depression. This means that the substancemust be supplied to the body slowly and continuously. Due to the poorbioavailability of <10%, oral sustained-release dosage forms(sustained-release tablets) cannot be used. When administeredtransdermally, the first-pass effect in the liver is avoided, theabsorption of the substance through the skin is good, and long-lasting,uniform blood levels can be achieved in this way if a suitabletransdermal formulation can be successfully developed. For thesereasons, the administration of fentanyl from a transdermal patch isachieving a steadily increasing market share in the treatment of severepain states.

In a transdermal system like Durogesic™, the fentanyl released from theformulation penetrates the skin barrier, enters the systemic circulationthrough the perfused subcutaneous tissue, and then develops itsanalgesic effect centrally by reaction at the opiate receptors in thebrain. Of course, due to the highly lipophilic character of the opioidanalogue, it becomes concentrated in the fatty tissue, from which it canlater be released into the circulation; this is referred to as a skindepot.

The penetration of a drug through the skin is largely determined by thephysicochemical properties of the substance. Mainly the octanol/waterpartition coefficient and the molecular size play a role here (R. O.Potts and R. H. Guy in: R. Gurny and A. Teubner: Dermal and TransdermalDrug Delivery, Wiss. Verlagsges., Stuttgart (1993)). Since the patientprefers to use an effective patch in a size that is as inconspicuous andsmall as possible, there is also the desire in this case to increase thepenetration rate, for which there are actually only two possibilities ifone does not wish to increase the skin by “microinjections”,microlesions, or the application of external energy sources (e.g.,iontophoresis or the like):

1. Facilitation of diffusion by the addition of penetration acceleratorsor the use of electric voltage (iontophoresis).

2. Increasing the drug concentration in the base even beyond thesolubility limit (supersaturation).

Substances used as penetration accelerators include alcohols, fattyacids, fatty alcohols, monohydric and polyhydric alcohols, laurocapram,and surfactants. However, many of these substances act by interferingwith the barrier function of the skin and are thus more or lessirritating to the skin. Nevertheless, numerous systems have beendescribed in the patent literature (cf. WO 89/10,108, WO 99/56,782, WO99/32,153, etc.).

Systems in which the active substance is present in supersaturated formare better tolerated. The maximum flux of a substance through the skinis usually limited by its solubility in the horny layer (stratumcorneum), which constitutes the skin penetration barrier. Thissaturation concentration will become established if the active substancein the vehicle, e.g., in the matrix of the transdermal system, is alsopresent in a concentration that corresponds to its solubility in thevehicle. One possible means of further increasing this so-called maximumthermodynamic activity consists in incorporating the drug in aconcentration that exceeds the solubility in the vehicle. This ispossible, for example, by incorporating the fentanyl in acrylatecopolymers (WO 20024386). However, supersaturation must be establishedso sensitively that the supersaturation is as high as possible but asstable as necessary, since, as is well known, supersaturated systems aremetastable and are converted to the saturated state by recrystallizationafter storage. This then has the disadvantage that, because of thecrystallization, these systems lead to product complaints due to thisdeficient aspect and due to a lack of adhesiveness. Close contactbetween the transdermal system and the skin is likewise necessary to getan effective fraction of fentanyl into the target area of the bloodcirculation.

Of course, as has already been mentioned, fentanyl is among the fewdrugs which, due to its physicochemical properties, permeates the skinbarrier very well and readily migrates into and accumulates in polymers.Since the therapeutic range of fentanyl is narrow and, in addition,there is the potential for addiction, as with all opioids, a furtherobjective of the development of a transdermal fentanyl patch is toincorporate as little substance as possible but as much as necessary tobe able to maintain a therapeutic blood level over a period of severaldays.

The objective of the present invention is to devise an improvedtransdermal therapeutic system of the type mentioned at the beginning.

In accordance with the invention, this objective is achieved by using anacrylate copolymer adhesive matrix that contains no penetrationaccelerators, such that the adhesive matrix is selected from thefollowing group:

-   -   (a) basic acrylate copolymer, especially acrylate copolymer with        hydroxyethyl acrylate units and with an organotitanium compound        as a crosslinking agent; and    -   (b) basic acrylate copolymer with vinyl acetate units and free        of crosslinking agents, especially acrylate copolymer with        hydroxyethyl acrylate units and vinyl acetate units.

It was discovered that the incorporation of the fentanyl as a base intoan acrylate copolymer crosslinked in a very specific way achievessaturation that is so stable that an effective product is obtainedwithout the necessity of adding penetration accelerators and at the sametime produces optimum adhesion to the skin of such a nature that duringclose contact between the dermal system and the outer skin barrier forseveral days up to a maximum of half a week, it can nevertheless beremoved again at any time without producing either a sensation of painor skin irritation.

Several acrylate copolymers produced by the company National Starch &Chemical, B.V., Zutphen, Netherlands (trade name: Durotak) were tested.It was found that a copolymer that contains small amounts of acrylicacid (Durotak 387-4350) and a graft copolymer (Durotak 87-9301 elite)that contains no acid or base groups but instead contains an acrylicoctylamide graft are too reactive and lead to significant decompositionof fentanyl within a very short time. Adhesives without functionalgroups (Durotak 87-4098) were found to be sufficiently stable, butadhesives with a small proportion of hydroxyethyl acrylate (Durotak387-2510) were clearly superior with respect to thermodynamic activityin the same concentration, which was apparent from better in vitropermeation rates in excised human skin mounted in Franz cells.

However, the use of an adhesive with hydroxyethyl acrylate (Durotak387-2510) in the presence of fentanyl leads to softening of the polymer,which in turn leads to excessive adhesive strength and “cold flow” ofthe adhesive matrix. Both are undesirable and make a patch unsuitable.

Several types of solvent-based adjustment of the adhesive strength ofthis very specific acrylate copolymer were tested. The copolymers wereproduced by the company National Starch & Chemical, B.V., Zutphen,Netherlands under the trade name Durotak. The formulation compositionsare reproduced in the following table (see next page): Example 1 inAccordance Comparative Comparative Comparative with the ParameterExample 1 Example 2 Example 3 Invention Durotak 387- X X X X 2510crosslinking — 0.5% 5% 0.5% agent aluminum polybutyl polybutyl acetyltitanate titanate acetonate adhesive 9.1 6.8 0.6 3.0 strength in vitro[N/25 mm] adhesive painful residues on adheres too good propertiesremoval, the skin weakly adhesive in vivo including when patch propertyabrasion of pulled off the horny layer

As can be seen, the wearing properties are achieved by crosslinking thebasic Durotak. There are many other possible means of influencing thecohesion and adhesive properties of these adhesives produced by NationalStarch & Chemical, B.V., Zutphen, Netherlands (Durotak 387-2510,387-2516), e.g., by titanium crosslinking agents, or by the addition ofsolids, such as Aerosil or talc, which have been very successfully usedin other systems (JP 2000-04447), or by the addition of other polymers,such as silicone, resins, or polyisobutylenes (WO 99/02141, WO93/00058), but when only the aforesaid adhesive Durotak 387-2510 isused, the use of polybutyl titanate produces the best result, which wassurprising. A specific, unknown type of incorporation of the activesubstance in the acrylate copolymer cavities, which are suitablyadjusted by crosslinking, is apparently produced, without binding orirreversible inclusion occurring. This is also evident from the factthat when polybutyl titanate is added to a formulation with fentanyl, anadhesive strength in vitro of about 3 N/25 mm results, as listed in thetable above, whereas the placebo, i.e., the formulation withoutfentanyl, has adhesive strength values that are higher by a factor of 2(6 N/25 mm).

The incorporation of the titanium crosslinking agent requires certainskills on the part of the expert. Depending on the supply source of thepolybutyl titanate, it may happen that this crosslinking agent must beworked into the formulation differently. For example, the crosslinkingagent produced by Aldrich (Germany), after being dissolved in a smallamount of ethanol, can simply be added all at once to the adhesivecompound that contains the active substance. If the same procedure isfollowed with the crosslinking agent produced by Synetix (Vertec™, UK),brown particles form in the laminate after a few weeks. Therefore, thiscrosslinking agent must be predissolved in heptane, and then ethanolmust be added to the mixture (mixing ratio 60:40), so that a 3% solutionof the crosslinking agent is obtained. This solution is slowly added tothe adhesive compound that contains the active substance, while themixture is being vigorously stirred. Only then is a matrix obtainedwhich is flawless even after storage.

It is recommended that the expert conduct preliminary tests to ensurethat he proceeds carefully with the addition of the crosslinking agent,so that increased decomposition of fentanyl does not occur andespecially that impurity D (European Pharmacopeia) does not form. Thisproduct already forms under conditions of stress storage of only onemonth at 40° C./75% relative humidity in an amount of about 1%, based onfentanyl. If the crosslinking agent is first homogenized in the adhesivecompound in the absence of the active substance, and then the dissolvedactive substance is added, a laminate that is free of contaminant Dshould be obtained.

Another possibility for reducing the softening effect of fentanyl on thebasic adhesive that is used is adjustment by admixture of a “harder”adhesive that is characterized by a content of vinyl acetate in theacrylate copolymer. This was successfully achieved by admixing anadhesive without functional groups, such as Durotak 87-4098. If Durotaktypes such as Durotak 87-2979 or 387-2287 or their successor types areused, then the ratio of 2-hydroxyethyl acrylate to vinyl acetate is nolonger 1:0.4 to 1:5, but rather 1:5.2 or 1:6, and they thus no longerhave the positive properties of high thermodynamic activity and theassociated high in vitro release and in vitro skin permeation of theadhesive mixture in accordance with the invention, in which the ratio ofhydroxyethyl acrylate to vinyl acetate is 1:0.4 to 1:5 in accordancewith the invention. The following table provides an overview of thevalues obtained with the formulations that were tested: Example 2 inExample 3 in Example 4 in Accordance Accordance Accordance ComparativeComparative with the with the with the Parameter Example 1 Example 2Invention Invention Invention Durotak 387-  0% 100% 90% 67% 50% 2510Durotak 87- 100%  0% 10% 33% 50% 4098 ratio of 2- 0% vinyl 0% 2-hydroxy-1:5 1:2.2 1:0.6 hydroxyethyl acetate ethyl acrylate acrylate: vinylacetate adhesive 3.9 9.1 8.3 7.1 6.7 strength in vitro [N/25 mm]adhesive adheres Painful removal, Good adhesive Good adhesive Goodproperties in relatively including property, slight property, slightadhesive vivo weakly horny layer adhesive borders adhesive bordersproperty aold flow strongly Not barely barely not present presentpresent present present in vitro -/29/-/ -/62/-/ -/69/-/ -/57/-/ notrelease [%] 46/103 88/104 89/95 75/84 determined of rated content after1/2/3/4/6 h

It is apparent that the admixture of the small amount of 1/10 of thetotal amount of adhesive already reduces the in vitro adhesiveproperties, which also manifests itself in the in vivo wearingproperties. The effect of the 10% addition on the in vitro release isstill comparable to the release from 100% Durotak 387-2510; however,when the admixed amount of Durotak 87-4098 is increased to 30%, therelease rate decreases. It was thus found, surprisingly, that theadmixture of 10% Durotak 87-4098 results in optimum adhesive propertieswith unchanged release. In the formulations in accordance with theinvention, actual application and placebo exhibit the same in vitroadhesive strengths.

The carrier of the matrix also plays an important role in the wearingproperties. Since, in the strongest dosage with a delivery rate of 100μg fentanyl per hour, the transdermal system already reaches a size of40 cm², which is considerable, a certain degree of flexibility is anadvantage with respect to wearing comfort.

Various transparent film materials were tested, which included, withrespect to the chemistry of the material, PET (polyester), BOPP(biaxially oriented polypropylene), PE (polyethylene, polyolefins), PU(polyurethane), and PS (polystyrene copolymer). Another importantconsideration here was the extent to which fentanyl exhibited migrationbehavior relative to the materials. It was found that PU achieved nocohesion with the adhesive matrix and was therefore unsuitable. PEshowed very pleasant wearing properties, but about 8-10% of the activesubstance migrated into this carrier film within less than one month at40° C./75% relative humidity and was thus no longer available fortransdermal absorption. Since fentanyl is very expensive as a rawmaterial, one would not wish to remedy this problem by adding morefentanyl during production. This approach would also be unsuitable forthe reason that the amount of fentanyl that migrates into the filmchanges over time. No migration was observed in PET (polyester),followed by BOPP, which was also preferred due to its somewhat greaterflexibility.

A siliconized polyester film with which the expert is already familiaris used as the protective film, e.g., Hostaphan RN 100 by Mitsubishi,Germany, siliconizing easy/easy. The protective film should not be toothin (at least 36 μm layer thickness, and preferably 100 μm layerthickness), so that even the larger systems of 30 cm² or more can stillbe easily handled by the patient.

The dermal therapeutic systems are preferably constituted in such a waythat they consist of a cover layer that is impermeable to the activesubstance, an adhesive layer that contains the active substance andadheres to the cover layer, and a removable protective layer.

This simplest form of a TDS can be produced in the manner well known tothe expert by mixing a solution of the adhesive or adhesive mixture in alow-boiling solvent with the active substance, uniformly applying themixture to a removable protective layer, quantitatively removing thesolvent by heating, and covering the resulting product with a carrier.The applied adhesive layer containing the active substance has athickness of 20 to 500 μm.

The following specific embodiments explain the invention in greaterdetail:

EXAMPLE 1 IN ACCORDANCE WITH THE INVENTION

0.056 g of polybutyl titanate in the form of a 3% solution ofheptane:ethyl alcohol 60:40 is slowly added with vigorous stirring to23.44 g of a 42% (w/w) solution of an acrylate adhesive (Durotak387-2510, National Starch & Chemical B.V., Zutphen, Netherlands), andthe resulting mixture is homogenized. 1.1 g of fentanyl dissolved in11.4 g of ethanol is added. The adhesive compound containing the activesubstance is homogenized by stirring for one hour and then spread with adoctor blade on a siliconized, 100-μm-thick polyester film (FL 2000,100μ, 1-S, Loparex B.V., Apeldoorn, Netherlands) in a wet coatingthickness of 310 μm. After drying (10 minutes at 70° C. and 5 minutes at100° C.), the clear and homogeneous laminate is backed with a polyesterfilm (Hostaphan RN15, Mitsubishi, Frankfurt, Germany). A patch with anarea of 10 cm² contains 5.5 mg of fentanyl with a matrix weight of 55.0g/m².

EXAMPLE 2 IN ACCORDANCE WITH THE INVENTION

A solution of 0.33 g of fentanyl in 3.7 g of ethanol is added to amixture of 6.29 g of a 42% (w/w) solution of the acrylate adhesiveDurotak 387-2510 and 0.86 g of a 38.3% (w/w) solution of the acrylateadhesive Durotak 87-4089. The solution is homogenized by stirring forone hour and then spread with a doctor blade on a siliconized,100-μm-thick polyester film (FL 2000, 100μ, 1-S, Loparex B.V.,Apeldoorn, Netherlands) in a wet coating thickness of 400 μm. Afterdrying (15 minutes at 70° C.), the slightly cloudy laminate is backedwith a BOPP film (Trespaphan NAA, 40 μm, Trespaphan, Frankfurt,Germany). A patch with an area of 10 cm² contains 5.5 mg of fentanylwith a matrix weight of 55.0 g/m².

EXAMPLE 3 IN ACCORDANCE WITH THE INVENTION

A solution of 0.33 g of fentanyl in 3.7 g of ethanol is added to amixture of 4.71 g of a 42% (w/w) solution of the acrylate adhesiveDurotak 387-2510 and 2.58 g of a 38.3% (w/w) solution of the acrylateadhesive Durotak 87-4089. The solution is homogenized by stirring forone hour and then spread with a doctor blade on a siliconized,100-μm-thick polyester film (FL 2000, 100μ, 1-S, Loparex B.V.,Apeldoorn, Netherlands) in a wet coating thickness of 400 μm. Afterdrying (15 minutes at 70° C.), the slightly cloudy laminate is backedwith a BOPP film (Trespaphan NAA, 40 μm, Trespaphan, Frankfurt,Germany). A patch with an area of 10 cm² contains 5.5 mg of fentanylwith a matrix weight of 55.0 g/m².

EXAMPLE 4 IN ACCORDANCE WITH THE INVENTION

A solution of 0.33 g of fentanyl in 3.7 g of ethanol is added to amixture of 3.54 g of a 42% (w/w) solution of the acrylate adhesiveDurotak 387-2510 and 3.87 g of a 38.3% (w/w) solution of the acrylateadhesive Durotak 87-4089. The solution is homogenized by stirring forone hour and then spread with a doctor blade on a siliconized,100-μm-thick polyester film (FL 2000, 100μ, 1-S, Loparex B.V.,Apeldoorn, Netherlands) in a wet coating thickness of 400 μm. Afterdrying (15 minutes at 70° C.), the slightly cloudy laminate is backedwith a BOPP film (Trespaphan NAA, 40 μm, Trespaphan, Frankfurt,Germany). A patch with an area of 10 cm² contains 5.5 mg of fentanylwith a matrix weight of 55.0 g/m².

The following embodiment shows that a patch produced in accordance withthe invention is bioequivalent to the originator product Durogesic in acrossover bioavailability study on six healthy subjects when the twopatch products are worn for three days each.

The formulation was the same as Example 1 in accordance with theinvention except that the backing consisted of a BOPP film (TrespaphanNAA, 40 μm, Trespaphan, Frankfurt, Germany) instead of a polyester film(Hostaphan RN15, Mitsubishi, Frankfurt, Germany). Each 10 cm² patchcontained 5.5 mg of fentanyl with a matrix weight of 55.0 g/m². Thecomparative patch was the Durogesic™ 25 μg membrane patch. Thepharmacokinetic results are compiled in the following table: Example 1in Accordance with the Invention Durogesic ™ 25 μg Name Fentanyl TDS 25membrane patch AUC (0-72 h) 26.723 pg/mL*h 24.911 pg/mL*h C max 496pg/mL 499 pg/mL T max 33 h (9 h) 42 h C peaks 24-42 h 30-71.8 habsorption somewhat faster — delivery rate same — BA (AUC) 107.2%(89-129.3%) somewhat lower BA (C max) 99.5% (80.1-123.5%) same ANOVA CV(AUC) 15.2% — n = 6 ANOVA CV (C max) 17.7% — n = 6

The skin tolerance and side effects were comparable for both products.

The graph in FIG. 1 shows the curves of the blood levels of the twoproducts.

The drying conditions specified in the examples were the conditions usedon the laboratory scale to produce the patches. The conditions used forproduction on a larger scale can differ from these laboratoryconditions. For example, in an experimental-scale operation, the productmay be conveyed at a rate of 2 m/minute through a tunnel drier with fourdrying zones with temperatures of 40° C., 60° C., 90° C. and 120° C.Production on a mass-production scale may involve different conditions,which are to be determined in scale-up tests.

1. Transdermal therapeutic system with a cover layer, an adhesive matrixthat contains fentanyl as the active ingredient, and a removableprotective layer, comprising an acrylate copolymer adhesive matrix thatcontains no penetration accelerators, such that the adhesive matrix isselected from the following group: (a) basic acrylate copolymer,especially acrylate copolymer with hydroxyethyl acrylate units and withan organotitanium compound as a crosslinking agent; and (b) basicacrylate copolymer with vinyl acetate units and free of crosslinkingagents, especially acrylate copolymer with hydroxyethyl acrylate unitsand vinyl acetate units.
 2. Transdermal therapeutic system in accordancewith claim 1, comprising a fentanyl concentration of 0.1 to 30 wt. % andespecially 5 to 18 wt. %, based on the weight of the adhesive matrixwith the active substance.
 3. Transdermal therapeutic system inaccordance with claim 1, comprising a residual content of fentanylsolvent, especially ethyl alcohol, of less than 0.25 wt. %, based on theweight of the adhesive matrix with the active substance.
 4. Transdermaltherapeutic system in accordance with claim 1, comprising (a) anacrylate copolymer comprising units that originate exclusively from2-ethylhexyl acrylate, methacrylate, and 2-hydroxyethyl acrylate, or (b)an acrylate copolymer comprising units that originate exclusively from2-ethylhexyl acrylate, methacrylate, 2-hydroxyethyl acrylate, and vinylacetate.
 5. Transdermal therapeutic system in accordance with claim 1,comprising an acrylate copolymer as the adhesive matrix, which can beproduced by drying at a temperature of about 70° C. or at a temperatureabove 70° C.
 6. Transdermal therapeutic system in accordance with claim1, characterized by the adhesive matrix comprising basic acrylatecopolymer, especially acrylate copolymer with hydroxyethyl acrylateunits and with an organotitanium compound as a crosslinking agent, whichcan be produced by crosslinking of the hydroxyl groups of the acrylatecopolymer and subsequent addition of the active substance. 7.Transdermal therapeutic system in accordance with claim 1, characterizedby the adhesive matrix comprising basic acrylate copolymer with vinylacetate units and free of crosslinking agents, especially acrylatecopolymer with hydroxyethyl acrylate units and vinyl acetate units,which can be produced from 2-ethylhexyl acrylate, methacrylate,2-hydroxyethyl acrylate, and vinyl acetate in a ratio of 2-hydroxyethylacrylate:vinyl acetate of 1:0.3 to 1:5, preferably 1:0.4 to 1:5, morepreferably 1:0.6 to 1:5, and most preferably 1:2.2 to 1:5, in each caseon the basis of the number of moles or on the basis of weight. 8.Transdermal therapeutic system in accordance with claim 7, characterizedby the adhesive matrix comprising basic acrylate copolymer with vinylacetate units and free of crosslinking agents, especially acrylatecopolymer with hydroxyethyl acrylate units and vinyl acetate units,which can be produced from 2-ethylhexyl acrylate, methacrylate,2-hydroxyethyl acrylate, and vinyl acetate in a ratio of 2-hydroxyethylacrylate:vinyl acetate of 1:1.5 to 1:3.0, and especially about 1:2.2, ineach case on the basis of the number of moles or on the basis of weight.9. Transdermal therapeutic system in accordance with claim 1,characterized by the adhesive matrix comprising basic acrylatecopolymer, especially acrylate copolymer with hydroxyethyl acrylateunits and with an organotitanium compound as a crosslinking agent withpolybutyl titanate as the crosslinking agent.
 10. Transdermaltherapeutic system in accordance with claim 9, comprising aconcentration of polybutyl titanate in an amount of 0.1 to 1%, andpreferably 0.4 to 0.6%, calculated on the basis of the number of moles.11. Transdermal therapeutic system in accordance with claim 1,comprising a layer thickness of the adhesive matrix of 20 to 500 μm. 12.Transdermal therapeutic system in accordance with claim 1, comprising acover layer based on polypropylene and especially by a biaxiallyoriented, longitudinally and transversely aligned polypropylene film.13. Transdermal therapeutic system in accordance with claim 1,comprising a cover layer based on polyester and especially by apolyester fabric.
 14. Transdermal therapeutic system in accordance withclaim 1, wherein the cover layer is designed as a matrix carrier.